Compositions and methods for lowering blood sugar using aryl sulphonylsemicarbazides containing heterocyclic acylamino groups

ABSTRACT

ORAL ANTIDIABETIC COMPOSITION ARE PROVIDED WHICH UTILIZE ARYL-SULPHONYL-SEMICARBAZIDES HAVING HETEROCYCLIC ACYLAMINO GROUPS TYPICAL EMBODIMENTS ARE REPRESENTED BY THE COMPOUNDS 4-(4-(B-(-METHYL-ISOXAZOLY-(5)-CARBONAMIDO)-ETHYL)-BENZENE-SULPHONYL)-1,1 -HEXAMETHYLENE-SEMICARBAZIDE, 4-(4-(B-(4,5-TETRAMETHYLENEISOXAZOLYL-(3)-CARBOXAMIDO)-ETHYL)-BENZENE -SULPHONYL)-1,1-HEXAMETHYLENE-SEMICARBAZIDE AND 4-(3(B-(5-METHYLISOXAZOLYL-(3)-CARBOXAMIDO)-ETHYL)BENZENE-SULPHONYL)-1,1 -HEXAMETHYLENE-SEMICARBAZIDE WHICH ARE ADMINISTERED IN DOSAGES OF 1-10 MG./KG. TO A DIABETIC HOST FORMULATED WITH EXCI-PIENTS AND TABLETED OR FILLED INTO GELATIN CAPSULES. IT IS KNOWN THAT ARYLSULPHONYL-UREA DERIVATIVES HAVE A BLOOD SUGAR-DEPRESSING EFFECT. IN PARTICULAR, N-(4-METHYLBENZENE-SULPHONYL)-N&#39;&#39;-BUTYL-UREA (TOLBUTAMIDE) HAS ACHIEVED GREAT IMPORTANCE AS A THERAPEUTIC AGENT BECAUSE OF ITS BLOOD SUGAR-DPRESSING EFFECT IN CONJUCTION WITH ITS GOOD COMPATIBILITY.

United States Patent Int. Cl. A61k 27/00 US. Cl. 424-267 13 Claims ABSTRACT OF THE DISCLOSURE Oral antidiabetic compositions are provided which utilize aryl-sulphonyl-semicarbazides having heterocyclic acylamino groups. Typical embodiments are represented by the compounds 4-{{4-{;3-[-methyl-isoxazolyl-(S)-carbonamido] ethyl} benzene sulphonyl}} 1,1 hexamethylene-semicarbazide, 4 [4 {fi-[4,5-tetramethyleneisoxazolyl (3) carboxamido] ethy1}-benzene-sulphonyl] 1,1 hexamethylene-semicarbazide and 4 [3- {5 [5 methylisoxazolyl (3) carboxamido]-ethyl}- benzene-sulphonyl] 1,1 hexamethylene-semioarbazide which are administered in dosages of 1-10 mg./kg. to a diabetic host formulated with excipients and tableted or filled into gelatin capsules.

It is known that arylsulphonyl-urea derivatives have a blood sugar-depressing effect. In particular, N-(4-methylbenzene-sulphonyl) N butyl urea (tolbutamide) has achieved great importance as a therapeutic agent because of its blood sugar-depressing elfect in conjunction with its good compatibility.

CROSS REFERENCE This is a divisional of Ser. No. 775,138, filed Nov. 12, 1968, now US. Patent No. 3,668,215.

DETAILED DESCRIPTION The present invention comprises sulphonyl-semicarbazides which contain heterocyclic acylamino groups and correspond to the formula:

R and R" are each hydrogen, halogen atoms, alkyl or aryl, aralkyl or cycloalkyl radicals unsubstituted or substituted by halogen, alkyl, alkoxy or trifiuoromethyl,

the grouping is a saturated or unsaturated, monocyclic or polycyclic radical which contains one or more hetero atoms, such as nitrogen, oxygen or sulphur, SO-- or S0 and which may be substituted by alkyl, alkoxy, hydroxy or oxo groups, and

X is oxygen, sulphur, nitrogen unsubstituted or substituted by hydrogen, alkyl or an aryl or aralkyl Radical which, in turn, is unsubstituted or substituted by halogen, alkyl, alkoxy or trifluoromethyl,

3,755,587 Patented Aug. 28, 1973 Y is a direct bond, a straight-chain or branched alkyl radical of 1 to 8 carbon atoms, and

n is a whole number from 0 to 4, and the substituents on the benzene ring may be in orthoor meta-, but preferably in para-position to one another.

in which R'" and R"" have the same meaning as above, as such or in salt form, with an arylsulphonamide derivative which contains heterocyclic acylarnino groups and corresponds to the formula:

R, R, R", X, Y and n have the same meaning as above,

and

A is a radical which is released in the course of the reaction with the hydrogen atom attached to the nitrogen of the hydrazine H NNR"-R"" with the elimination of a compound HA, or with corresponding arylsulphonyl-isocyanate:

0 R Rggqiantas \X/ A being, for example, halogen, azido, alkoxy, aryloxy, alkylmercapto, arylmercapto, unsubstituted or substituted amino, cyclic amino or acylamino; or

(b) Reacting an arylsulphonamide of the formula:

in which R, R, R", X, Y and n have the same meaning as above, as such or in the form of their alkali metal salts, with a hydrazine derivative of the formula:

S OgNHg in which B is a radical which reacts in the course of the reaction with a hydrogen atom of the sulphonamide group or with the alkali metal atom M of the corresponding sulphonamide alkali metal salt with the elimination of HB or MB; B is, for example, halogen, azido, alkoxy, aryloxy, alkylmercapto, arylmercapto, unsubstituted or substituted amino, cyclic amino or acylamino; or

(c) Reacting an arylsulphonyl halide of the formula:

3 in which:

R, R, R", X, Y and n have the same meaning as above,

and Hal is a halogen atom, preferably chlorine or bromine,

with a semicarbazide of the formula:

H NCONHNR"'R""; or

(d) Converting an arylsulphonyl compound of the formula:

semicarbazide of the formula:

l H-NY SOZNH(HJNHN/ in which R, R", R"' and Y have the same meaning as above, with a carboxylic acid or derivative:

in which:

R, R, K and n have the same meaning as above, and

R" is a group which reacts with the hydrogen atom on the amino group of the reaction component mentioned above with the elimination of R"'H; R" is, for example, hydroxy, alkoxy, aryloxy or halogen, preferably chlorine; or

(f) Oxidizing a benzene sulphenyl semicarbazide (m =0) or benzene-sulphinyl-semicarbazide (112:1) of the formula:

in which R, R, R", R'", R'', X, Y and n have the same meaning as above; or v (g) Hydrolyzing a parabanic acid derivative of the formula:

in which R, R, R", R', R'', X, Y and n have the same meaning as above.

As carboxylic acids from which the heterocyclic acyl radical in the final products of the invention are derived, there may be used, for example:

isoxazole-(S )-carboxylic acid, 3-methylisoxazole-(5)-carboxylic acid, 5-methylisoxazole- (3 -carboxylic acid, 5-methyl-3-phenylisoxazole-(4)-carboxylic acid,

3 (2',6'-dichlorophenyl) -5 -methyl isoxazole- (4) carboxylic acid,

3,S-dimethyl-isoxazole-(4)-carboxylic acid, isoxazole- (3 -carboxylic acid, isoxazole-(4)-carboxylic acid, 3-methylisoxazole-(4)-carboxylic acid, S-methylisoxazole-(4)-carboxylic acid, 4,5-dimethylisoXazole-(3)-carboxylic acid, 5-hexylisoxazo1e-( 3 -carboxylic acid, 5-octylisoxazole-(3)-carboxylic acid, 5-phenylisoxazole- 3 -carboxylic acid, 5-tert.-buty1-3-phenyl-isoxazole-(4)carboxylic acid, 3,5-diphenylisoxazole-(4)-carboxylic acid, 3-ethyl-5-rnethylisoxazole-4-carboxylic acid, S-methyl-3-phenylisoxazole-(4)-carboxylic acid, 3-phenylisoxazole- (4 -carboxylic acid, 5-phenylisoxazole-(4)-carboxylic acid, 4-chloro-3-methylisoxaz0le-(4)-carboxylic acid, 3-phenylisoxazole- 5 -car-boxylic acid, 4-phenyl-isoxazole-(5)-carboxylic acid, 3,4-tetramethylene-isoxazole- (5 -carboxylic acid, 4,5-tetramethylene-isoxazole-( 3 )-carboxylic acid, B-isoxazolyl- (5 -propionic acid, 3,5-dimethyl-isoxazolyl-(4)-acetic acid, isothiazole-(3)-carboxylic acid, 4-phenyl-isothiazole-(3)-carboxylic acid, 5-phenyl-isothiazole- (3 -carboxylic acid, isothiazole-(4)-carboxylic acid, 3-methyl-isothiazole-(4) -carboxylic acid, 3,5-dimethyl-isothiazo1e-(4)-carboxylic acid, 3,5-dimethy1-isothiazo1e-(4)-carboxylic acid, 3-methy1-S-benzylisothiazole-(4)-carboxylic acid, 3-methyl-S-ethyl-isothiazole-(4) -carboxylic acid, 3-rnethyl-5-propyl-isothiazole-(4)-carboxylic acid, 3-ethyl-5-phenyl-isothiazoie-(4)-carboxylic acid, isothiazole-(S -carboxylic acid, 3-methyl-isothiazole-(5)-carboxylic acid, 4-methy1-isothiazole- (5 -car-boxylic acid, pyrazole- 3 -carboxylic acid, pyrazole-(4)-carboxylic acid, l-methyl-pyrazole-(S)-carboxylic acid, 4-methylpyrazole (5 -carboxylic acid, 3-methylpyrazole- (4) -carboxylic acid, V 3-methylpyrazole-( 5 -carboxylic acid, l-phenylpyrazole-(3)-carb0xy1ic acid, 1-phenylpyraz0le-(4)-carb0xylic acid, l-phenylpyrazole- (5 carboxylic acid, 4-phenylpyrazole- (3 )-carboxylic acid, 3-phenylpyrazole-(4)-carboxylic acid, S-phenylpyrazole- (5 -carboxylic acid, 3-methyl-l-phenylpyrazole-(4)-carboxylic acid, S-methyl-l-phenylpyrazole-(4)-carboxy1ic acid, S-methyl-1-phenylpyrazole-(3)-carboxylic acid, B-methyl-l-phenyl-pyrazole-(S)-carboxylic acid, l-methyl-5-phenyl-pyrazole-(3)-carboxylic acid, 1-methyl-5-phenyl-pyrazole- (5 -carboxylic acid, 4-methy1-3-phenylpyrazole-(5)-carboxylic acid, 3-rnethyl-S-phenyl-pyrazole-(4)-carboxy1ic acid, 1,4-dimethyl-pyrazole-( 3) -carboxylic acid, 1,4-dimethyl-pyrazole-(5)-carboxy1ic acid, 1,5-dimethyl-pyrazole-(3)-carboxy1ic acid, 1,3-dimethyl-pyrazole-(5)-carboxy1ic acid, 1,4-dimethy1-pyrazole- 5 -carboxylic acid, 3,5-dimethyl-pyrazole-(4)-carboxylic acid, 4,5-dimethyl-pyrazole-( 3 )-carboxylic acid.

Suitable compounds for introducing the sulphonamide component into the final products according to the invention are, for example:

B-aminobenzene-sulphonamide, 4-aminobenzene-sulphonamide, 4aminomethylbenzene-sulphonamide, 4-(u-aminoethyl)-benzene-sulphonamide, 4- fl-aminoethyl) -benzene-sulphonamide, 4- a-aminopropyl) -benzene-sulphon amide,

4-(fi-aminopropyl)-benzene-sulphonamide,

4- ('y-aminopropyl-sulphonamide) 4-(a-amino-u,a-dimethylmethyl)-benzene-sulphonamide, 4-methylaminobenzene-sulphonamide and similar compounds in the form of their base or of salts with acids.

Suitable hydrazines from which the group in the products according to the invention are derived, are, for example:

l-amino-pyrrolidine, l-amino-piperidine, N-amino-morpholine, 1-amino-hexarnethylene-imine, 1-amino-4-methyl-piperideine- (4) N-aminothiamorpholine, N-aminothiamorpholine-S,S-dioxide, N-amino-3-methyl-thiamorpholine-S,S-dioxide, 3-amino-3-azabicyclo[3,2,0] -heptane, 3-amino-3-azabicyclo [3 ,2,1]octane, 6-amino-6-azabicyclo [3 ,2,1]-octane, 3-amino-3-azabicyclo [3 ,2,2] -nonane, 3-amino-3-azabicyclo- [3 ,3 ,1 ]-nonane, Z-amino-Z-azabicyclo-[2,2,2] -octane, N-amino-nortropane, N-amino-granatanine and their alkyl-substitution products, N-amino-camphidine, N-amino-4,7-endocyclo-propylene-A -hexahydro-isoindole, N-amino-4,7-endocyclobutenylene-A -hexahydro-isoindole, N-amino-4,7-endocyclobutylene-octahydro-isoindole.

Depending on the method of operation, the hydrazines can be used as such or in the form of their derivatives such as carbazidic acid chlorides, carbazidic acid esters or carbazidic acid azides.

The reactions are carried out Without or in suitable solvents or diluents; depending on the reactivity of the components, the reaction is itself exothermic or its progress must be brought about or furthered by the use of elevated temperatures. The final products can be converted into therapeutically applicable salts.

Products which contain one or more optically active carbon atoms can be obtained not only in the form of the racemates, but also in their optically active forms, either by using for their preparation, from the start, a corresponding optically active bicyclic amino compound or by subjecting racemic intermediates or final products to a racemate resolution.

EXAMPLE 1 (a) 92.8 g. (0.3 mole) of 4-{5-[3-methyl-isoxazolyl- (5) carbonamido]-ethyl}-benzene sulphonamide (prepared from 3-methyl-isoxazole-(5)-carboxylic acid chloride and 4-(fl-aminoethyl)-benzene-sulphonamide hydrochloride in pyridine, M.P. 219-220 C.) are heated in 1.5 litres of methyl ethyl ketone with 82.8 g. (0.6 mole) of pulverized potassium carbonate under reflux for 40 minutes while stirring. After cooling to room temperature, 47.3 g. (0.5 mole) of chloroformic acid methyl ester are added dropwise, the mixture is stirred at room temperature for 15 minutes and under reflux for 4 hours, the product is filtered off with suction while hot and washed with methyl ethyl ketone. The residue is dissolved in water, the solution clarified with activated charcoal, and the filtrate acidified with hydrochloric acid. The resultant precipitate is filtered off with suction, washed with water, and dried. 85.6 g. (77% of theory) of N-{{4-[3- methyl-isoxazolyl carbonamido-ethyl}-benzene-sulphonyl}}-methyl-urethane are obtained in the form of a colorless finely crystalline powder of M.P. 184 C.

(b) 7.3 g. (0.02 mole) of this compound are dissolved in 150 ml. of methanol, 2.5 g. (0.022 mole) of N-aminohexamethylene-imine are added, and the methanol is distilled oif, finallyunder reduced pressure; the residue is finally heated at to C. for 30 minutes, whereupon it solidifies to form a solid mass which is recrystallized from ethanol. 6.2 g. (69% of theory) of 4-{{4-{/3- [3-methyl isoxazolyl-(S)-carbonamido]-ethyl}-benzenesulphonyl}} 1,1 hexamethylene-semicarbazide are obtained in the form of colorless crystals of M.P. 194 C.

EXAMPLE 2 (a) By analogy to Example 1(a), there is obtained from 4-{5- [5-methyl-isoxazolyl-(3 )-carbonamido]-ethyl}- bcnzene-sulphonamide (prepared from S-methyl-isoxazole-(3)-carboxylic acid chloride and 4-(fl-aminoethyl)- benzene-sulphonamide hydrochloride, M.P. 2l3-214 C. in pyridine) and chloroformic acid methyl ester, in a yield of 69%, the compound N-{{4-{ 3-[S-methyl-isoxazolyl- (3) carbonamido]-ethyl}-benzene sulphonyl}}-methylurethane in the form of colorless crystals of M.P. 173 C.

(b) From the sulphonyl-urethane described above and N-amino-hexamethylene-imine, there is obtained, by analogy to the method described in Example 1(b), in a yield of 70%, the compound 4-{{4-{ 3-[5-rnethyl-isoxazolyl-(3)-carbonamido]-ethyl}-benzene sulphonyl}}-1,1- hexamethylene-semicarbazide in the form of colorless crystals of M.P. 189 C.

EXAMPLE 3 By analogy to Example 1(b), there is obtained, from the sulphonyl-urethane prepared according to Example 1(a) and N amino isoquinuclidine, the compound 4{{4-{B- [3 methyl isoxazolyl (5) carbonamido]-ethyl}- benzene sulphonyl}} 1,1 [1',4'-ethano)-pentamethylene-semicarbazide] in the form of colorless crystals of M.P. 197 C.

EXAMPLE 4 By analogy to Example 1(b), there is obtained, from the sulphonyl-urethane prepared according to Example 2(a) and N-amino-isoquinuclidine, the compound 4-{{4- {5-[5 methyl isoxazolyl 3) carbonamido] ethyl}- benzene sulphonyl}} 1,1-[1,4' ethano]-pentamethyl ene-semicarbazide in the form of colorless crystals of M.P. 190 C.

Furthermore, with N aminopiperidine, the compound 4 {{4 {1 [s methylisoxazolyl-(3)-carbonamido]- ethyl} benzene sulphonyl}} 1,1 pentarnethylene-semicarbazide of M.P. 185 C.; with N-aminomorpholine, the compound 4 {{4 {e [5 methylisoxazolyl-(3)-carbonamido1-ethyl} benzene sulphonyl}} 1,1 (oxydiethylene)-semicarbazide of M.P. 174 C.', with 3-methyl-4- aminothiomorpholine 1 dioxide, the compound 4-{{4- i [5 methylisoxazolyl (3) carbonamido]-ethyl}- benzene sulphonyl}} 1,1 (2' methyl sulphonyl-diethylene)-semicarbazide of M.P. C.

EXAMPLE 5 4 [3 methylisoxazolyl (5) carboxamido]-benzenesulphonarnide, M.P. 249 C. (prepared from 3-methylisoxazole (5) carbonic acid chloride and 4 aminobenzenesulphonamide hydrochloride in pyridine), by analogy to Example 1(a) with chloroformic acid methyl ester is transformed into the corresponding sulphonylurethane of M.P. 244 C. Similarly to Example 1(b) there is obtained therefrom with N-aminohexamethyleneimine, the compound 4 {4 [3 methylisoxazolyl-(5)-carboxamido] benzenesulphonyl} 1,1 hexamethylene semicarbazide as a colorless fine crystalline powder of M.P. 227 C., and with N amino morpholine, the compound 4 {4 [3 methylisoxazolyl (3) carboxamido]-benzene-sulphonyl} 1,1 (oxydiethylene)-semicarbazide of M.P. 243 C.

EXAMPLE 6 4 [5 methylisoxazolyl (3) carboamidomethyl]- benzenesulphonamide of M.P. 210 C. (prepared from 5- methylisoxazole (3) carbonic acid chloride and 4- aminomethyl benzenesulphonamide hydrochloride in pyridine) is by analogy to Example 1(a) with chloroformic acid methyl ester transformed into the corresponding sulphonyl-urethane, i.e., N {{4 methylisoxazolyl (3) carbonamido] ethyl benzene sulphonyl}}- methyl-urethane, of M.P. 172 C. Similarly to Example 1(b) there is obtained therefrom with N-aminohexa methyleneimine the compound 4 {4 [5 methylisoxazolyl (3) carbonamidomethyl]-benzenesulphonyl}- 1,1 hexamethylene semicarbazide of M.P. 180 C., as as colorless fine crystalline powder, and with N-aminomorpholine, the compound 4-{4-[5-methylisoxazolyl-(3)- carboxamidomethyl] benzenesulphonyl} 1,1 (oxydiethylene)-semicarbazide of M.P. 225 C.

EXAMPLE 7 4 {a [5-methylisoxazolyl-(3)-carbonamido]-ethyl}- benzene-sulphonamide of M.P. 169 to 171 C., (prepared from 5 methylisoxazole (3) carbonic acid chloride and 4 (u aminoethyl) benzene-sulphonamide in pyridine) by analogy to Example 1(a) with chloroformic acid methyl ester is transformed into the corresponding sulphonylmethylurethane of M.P. F. 74 C. Therefrom there is obtained similarly to Example 1(b) with N-aminohexamethyleneimine the compound 4 {{4 {oz [S-methylisoxazolyl (3) carbonamido] ethyl} benzene-sulphonyl}} 1,1 hexamethylene semicarbazide of M.P.

181 C., as a colorless fine crystalline powder.

EXAMPLE 8 Similarly to Example 2(a) there is obtained from 4-{m- [5 methylisoxazolyl (3) carboxamido] propyl}- benzenesulphonamide (prepared from 5 methylisoxazole- 3-carbonic acid chloride and 4-(a-aminopropyD-benzenesulphonamide hydrochloride in pyridine of M.P. 165 C.) and chloroformic acid methyl ester, the compound N [4 {a [5 methylisoxazolyl-(3)-carboxamido]- propyl} benzenesulphonyl] methylurethane of M.P. 146148 C., and therefrom similarly to Example 2(b) with N aminohexamethylene-imine, the compound 4-[4- {a [4 methylisoxazolyl (3) carboxamido] propyl}- benzenesulphonyl] 1,1 hexamethylene-semicarbazide of M.P. 161 C.

EXAMPLE 9 Similarly to Example 2(a) there is obtained from 4-{5- [4,5 tetramethylene 'isoxazolyl (3) carboxamido]- ethyl} benzenesulphonamide (prepared from 4,5-tetramethylene isoxazole 3 carbonic acid chloride and 4- (B aminoethyl) benzenesulphonamide hydrochloride, in pyridine of M.P. 175 C.) and chloroformic acid methyl ester the compound N-[4-{p-[4,S-tetramethylene-isoxazolyl (3) carboxamido] ethyl} benzenesulphonyl]- urethane of M.P. 172 C. and therefrom by analogy to Example 2(b) with N aminohexamethyleneimine, the compound 4 [4 {13 [4,5 tetramethylene-isoxazolyl- (3 )-carboxamido]-ethyl} benzenesulphonyl] 1,1 hexamethylene-semicarbazide of M.P. 180 C.

EXAMPLE Similarly to Example 2(a) there is obtained from 4- {B-[LS dimethyl pyrazolyl-(3)-carboxamido]-ethyl}- benzene-sulphonamide (produced from 1,5-dimethylpyrazole-3-carbonic acid chloride and 4( 8-aminoethyl)-benzenesulphonamide-hydrochloride in pyridine of M.P. 225 C.) and chloroformic acid methyl ester, the compound N-[4-{;8-[1,5-dimethylpyrazolyl-( 3) carboxamido] ethyl}-benzenesulphonyl]-methyl-urethane of M.P. 211 C., and therefrom similarly to Example 203) with hexamethyleneimine, the compound 4-[4-{;9-[1,5-dimethylpyrazolyl-(3)-carboxamido]-ethyl}-benzenesulphonyl] 1,1-hexamethylene-semicarbazide of M.P. 186188 C.

EXAMPLE 1 1 Similarly to Example 2(a) there is obtained from 4- 8-[3 methylisothiazolyl (5) carboxamido] ethyl}- benzenesulphonarnide (prepared from 3-methylisothiazole-(5)-carbonic acid chloride and 4(B-aminoethyl)- benzenesulphonamidehydrochloride in pyridine of M.P. 190 C.) and chloroforrnic acid methyl ester, the compound N-[4-{ 8-[3 methylisothiazolyl (5) carboxamido] ethyl} benzenesulphonyl] methylurethane of M.P. 161 C., and therefrom similarly to Example 2(b) with N-aminohexamethyleneimine, the compound 4-[4- {lit-[3 methylisothiazolyl (5) carboxamido]-ethyl}- benzenesulphonyl] 1,1 hexamethylene semicarbazide of M.P. 171 C.

EXAMPLE 12 Similarly to Example 2(a) there is obtained from 3- {fl-[S methylisoxazolyl (3) carboxamido]-ethyl}- benzenesulphonyl (prepared from 5-methyl-isoxazole-3- carbonic acid chloride and 3-(fl-amidoethyl)-benzenesulphonamidehydrochloride in pyridine of M.P. 115 C.) and chloroforrnic acid methyl ester, the compound N-[3- {ti-[5 methylisoxazolyl-(3)-carboxamido] ethyl}-benzenesulphonyl]-methylurethane of M.P. 143 C., and therefrom with N-amino-hexamethylene-imine like 2(b), the compound 4-[3-{5-[5 methylisoxazolyl (3) carboxamido1-ethyl} benzenesulphonyl] 1,1 hexamethylene-semicarbazide of M.P. 183 C.

The blood sugar lowering action of 4-[4-{fi-[5-methylisoxazolyl (3) carb0xamido1-ethyl} benzenesulphonyl] 1,1 hexamethylene semicarbazide, in comparison to 4-(4-tolylsulphonyl) 1,1 'hexamethylene-semicarbazide (Tolazamide) as to ingestion at the start of the tests of fed rats:

Blood sugar in percent of the starting value 4-{4-{fl-[5-methylisoxazolyl-(3)-carboxamido]- ethyll-benzenesulphonyl} 1,1-hexarnethylene-semiearbazide Tolazamide Dosage, mgJkg 0. 01 0. 1 1 10 Hours after administration:

The toxicity of the material 4-[4-{5-[S-methylisoxazolyl- (3)-carboxamido]-ethyl}-benzenesulphonyl] 1,1 hexamethylene-semicarbazide is in rats only half of the 10 g./kg. of body weight for oral administration as compared to Tolazamide. For therapeutic purposes, this substance is orally administered in tablet or capsule form, for example, in dosages of 1 to 10 mg. per person,

Tablets semicarbazide 1 Aerosil 10 Cornstarch 20 Magnesium stearate 1 Lactose 68 Hard gelatin capsules The finely pulverized active substance is mixed With the requisite additives and filled into capsules so that each capsule contains the following substances:

Mg. 4 [4 3 [5-methylisoxazolyl-(3)-carboxamido]- ethyl} benzenesulphonyl] 1,1 hexamethylenesemicarbazide 1 Lactose 79 Cornstarch 10 9 What is claimed is: 1. A blood sugar lowering pharmaceutical composition for oral administration comprising (a) a blood sugar lowering amount of a compound of the formula:

R and R" are each hydrogen, halogen, alkyl of 1 to 8 carbon atoms, or together tetramethylene in the 4,5 position;

R' and R" together are alkylene of 4 to 6 carbon atoms unsubstituted or substituted by methyl; and

X is oxygen;

Y is a direct bond or straightor branched-chain alkyl of 1 to 3 carbon atoms; and

n is a whole number from to 4, the substituents on the benzene ring being ortho-, metaor parato one another,

or a pharmaceutically acceptable non-toxic alkali metal or alkaline earth metal salt thereof; and (b) a pharmaceu tical carrier.

2. A composition according to claim 1 wherein said compound is in the form of an alkali metal or alkaline earth metal salt.

3. A composition according to claim 1 wherein the substituents in the benzene ring of said compound are para to each other.

4. A composition according to claim 1 which is a tablet or capsule and in which said compound is 4-{{4-{B-[3- methyl-isoxazolyl (5)-carboxamido]-ethyl}-benzenesulphonyl}}-l,1-hexarnethylene-semicarbazide.

5. A composition according to claim 1 which is a tablet or capsule and in which said compound is 4-[4-{fl-[4,5 tetramethylene-isoxazolyl (3)-carboxamido]-ethyl}-benzenesulphonyl]-l,l-hexamethylene-semicarbazide.

6. A composition according to claim 1 which is a tablet or capsule and in which said compound is 4-[3-{6-[5- methyl-isoxazolyl-( 3) carboxamido]-ethyl}-benzenesulphonyl]-1,l-hexamethylene-semicarbazide.

7. A composition according to claim 1 which is a tablet or capsule and in which said compound is 4-{{4-{[5- methyl-isoxazolyl (3) carboxamido]-ethyl}benzenesulphonyl}}-1, 1-hexamethylene-semicarbazide.

8. A composition according to claim 1 which is a tablet or capsule and in which said compound is 4-{{4-{ 3-[5- methyl-isoxazolyl (3) carboxamido]-ethyl}-benzenesulphonyl}}-l,l-pentamethylene-semicarbazide.

9. A composition according to claim 1 which is a tablet or capsule and in which said compound is 4-{4-[3-methylisoxazolyl (5) carboxamido]-benzenesulphonyl}-l,1- hexamethylene-semicarbazide.

10. A composition according to claim 1 which is a tablet or capsule and in which said compound is 4-{4-[5-methylisoxazolyl (3 )-carboxamido-methyl] -benzenesulphonyl}- 1, l-hexamethylene-semicarbazide.

11. A composition according to claim 1 which is a tablet or capsule and in which said comopund is 4-{{4-{u-[5 methyl-isoxazolyl (3)-carboxamido]-ethyl}-benzenesulphonyl}}-1,l-hexamethylene-semicarbazide.

12. A composition according to claim 1 which is a tablet or capsule and in which said compound is 4-[4-{a-[4- methyl-isoxazolyl- (3 )-carboxamido] -propyl}-benzenesul phonyl1-l,1-hexarnethylene-semicarbazide.

13. The method of lowering blood sugar in an animal which comprises administering to said animal a blood sugar lowering amount of a compound of the formula:

R is hydrogen or methyl;

R and R" are each hydrogen, halogen, alkyl of 1 to 8 carbon atoms, or together tetramethylene in the 4, 5 position;

R' and R"" together are alkylene of 4 to 6 carbon atoms unsubsttiuted or substituted by methyl; and

X is oxygen;

Y is a direct bond or straightor branched-chain alkyl of 1 to 3 carbon atoms; and

n is a whole number from 0 to 4, the substituents on the benzene ring being ortho-, metaor parato one another,

or a pharmaceutically acceptable non-toxic alkali metal or alkaline earth metal salt thereof.

References Cited FOREIGN PATENTS 1,176,310 1/1970 Great Britain 260307 H JEROME D. GOLDBERG, Primary Examiner US. Cl. X.R.

V UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 755 587 Dated August Z8 l973 l HANS PLUMPE, ET. AL.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the heading of the patent, insert Cleims priority November 25, 1967, Germany No. P 16 70 952.7

Signed and sealed this 13th day, of August 1974.

(SEAL) Attest:

MCCOY M. GIBSON, JR. C. MARSHALL DANN Attesting Officer Commissioner of Patents )RM PC4050 (10-69) USCOMM-DC 60376-P69 u.s. covzmmzm- "mums omc: I": o-ue-au, 

